Enhancement of effectiveness of 5-fluorouracil in treatment of tumor metastases and cancer

ABSTRACT

Tumor growth and metastases in cancer patients are inhibited by administration of a combination therapy including effective amounts of 5-Fluorouracil and a methylol transfer agent such as taurolidine, taurultam or mixtures thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of Ser. No. 12/016,294, filedJan. 18, 2008, now U.S. Pat. No. 7,910,580, which is a continuation ofU.S. application Ser. No. 10/660,798, filed Sep. 12, 2003, now U.S. Pat.No. 7,345,039, which is a continuation-in-part of U.S. application Ser.No. 10/281,138, filed Oct. 28, 2002, now U.S. Pat. No. 6,815,441, whichis a continuation-in-part of U.S. application Ser. No. 09/993,896, filedNov. 27, 2001, now abandoned, which claims the benefit of U.S.Provisional Application No. 60/253,138, filed Nov. 28, 2000. U.S.application Ser. No. 10/281,138 is a divisional of U.S. application Ser.No. 09/583,902, filed Jun. 1, 2000, now U.S. Pat. No. 6,479,481 B1,which claims the benefit of U.S. Provisional Application No. 60/182,200,filed Feb. 14, 2000, U.S. Provisional Application No. 60/174,607, filedJan. 5, 2000, U.S. Provisional Application No. 60/167,681, filed Nov.29, 1999, U.S. Provisional Application No. 60/151,050, filed Aug. 27,1999 and U.S. Provisional Application No. 60/137,421, filed Jun. 4,1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of treating tumor metastasesand cancer.

2. Description of the Background Art

5-Fluorouracil (5-FU) is an antineoplastic drug with clinical activityin a variety of tumors, such as cancers of the colon and rectum, headand neck, liver, breast, and pancreas. One problem with 5-Fu is itsextreme toxicity. Since 5-FU targets rapidly dividing cells, the primarytoxic side effects are on bone marrow, intestinal mucousa and oralmucousa. Thus, leukocyte and platelet count decreases substantiallyafter administration. Other side effects include stomatitis, diarrhea,nausea and vomiting. Neurological side effects include somnolence andataxia. Other side effects include chest pain, myocardial necrosis andischemia. Inflammatory reactions such as acute and chronicconjunctivitis leading to tear duct stenosis and ectropion also occur.

Monotherapy with 5-FU only results in tumor remission in about 20-25% ofpatients, and the average remission time is only about 6-8 months.

Although combination chemotherapy with 5-FU and other antineoplasticagents has been proposed, typically no substantive additional benefit isprovided by the other antineoplastic agents over treatment with 5-FUalone.

Thus, there remains a significant need in the art for new and improvedcancer treatment therapies.

SUMMARY OF THE INVENTION

In accordance with the present invention, tumor growth and metastasis isinhibited in a cancer patient by administering to said patient acombination therapy comprising effective amounts of 5-FU and a methyloltransfer agent.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that methylol transfer agents such astaurolidine and taurultam substantially enhance or augment theantineoplastic effects of 5-FU in a combination therapy for inhibitingtumor metastases and treating cancer in patients. Such methylol transferagents also substantially reduce the toxic side effects of 5-FU.

5-FU when used in accordance with the present invention includesbiologically active derivatives or substantial equivalents thereof.

Methylol transfer agents include methylol-containing compounds such astaurolidine and taurultam. The compounds taurolidine and taurultam aredisclosed in U.S. Pat. No. 5,210,083. Other suitable methylol-containingcompounds may be found among those identified in PCT Publication No. WO01/39763. Particularly preferred methylol transfer agents forutilization in accordance with the present invention are taurolidine,taurultam, biologically active derivatives thereof and mixtures thereof.

Particularly preferred embodiments involve treatment of cancers selectedfrom the group consisting of colon cancer, rectal cancer and colo-rectalcancer, as well as inhibition of tumor metastases thereof.

Other cancers to which the combination therapy of the present inventionis effective may include other carcinomas, sarcomas or lymphomas,cancers of the head and neck, liver cancer, breast cancer and pancreaticcancer. Cancers to which the present invention may be applicable includeglioma, neuroblastoma, astrocytoma, carcinomatous meningitis, ovariancancer, prostate cancer, central nervous system (CNS) cancer, lungcancer, gastric cancer, esophageal cancer, urinary bladder cancer,leukemia, lymphoma, melanoma, renal cell cancer and metastases thereof.

Effective daily dosage amounts of 5-FU may be in the range of about0.1-1,000 mg per pharmaceutical dosage unit. Effective dosage amounts of5-FU also may be in the range of about 100-5,000 mg/m² body surfacearea, preferably about 200-1,000 mg/m² body surface area, morepreferably about 500-600 mg/m² body surface area. 5-FU typically isprovided in 250 mg or 500 mg ampules for injection, or 250 mg capsulesfor oral administration.

Effective dosage amounts of a methylol transfer agent in accordance withthe present invention may comprise pharmaceutical dosage units withinthe range of about 90.1-1,000 mg/kg. Preferred dosages may be in therange of about 10-20 grams taurolidine, taurultam or a mixture thereof,per administration.

Pharmaceutical dosage units of the combined therapy of the presentinvention may be administered by any suitable route, which include oral,topical or peritoneal administration, e.g., subcutaneously,intraperitoneally, intramuscularly, or intravenously, e.g., by infusionor injection.

In preferred embodiments, 250 ml of taurolidine 2% solution isadministered by intravenous infusion about 1-6 times per day, morepreferably about 2-4 times per day, during a treatment period,concurrently or sequentially with administration of 5-FU at a preferreddosage within the range of about 500-600 mg/m² body surface area. Inaccordance with one embodiment, 5-FU is administered by bolusintravenous injection at a dosage of 500 mg/m² body surface area, 1-3days per week for a total of three weeks, during a treatment periodincluding administration of taurolidine and/or taurultam. In analternative embodiment, a 600 mg/m² intravenous bolus injection isadministered 1-2 times per week during a three week treatment period,along with administration of taurolidine and/or taurultam as indicatedabove.

The present invention also is directed to a combination of 5-FU and amethylol transfer agent, in effective amounts for simultaneous, separateor sequential use for inhibiting tumor metastasis in a cancer patient.The invention also is directed to pharmaceutical combinations includingpharmaceutical dosage units comprising effective amounts of5-Fluorouracil and a methylol transfer agent for inhibiting tumormetastasis in a cancer patient, as well as to pharmaceuticalcompositions comprising such combinations.

In contrast with other antineoplastic agents, methylol transfer agentssuch as taurolidine and taurultam surprisingly and substantially enhanceor augment the antineoplastic effects of 5-FU, and substantially reducethe extreme toxic side effects of 5-FU. Accordingly, with a combinationtherapy of 5-FU and a methylol transfer agent such as taurolidine and/ortaurultam, the amount of 5-FU can be reduced to achieve the sameactivity as larger dosages of 5-FU alone, while encountering fewer toxicside effects. Alternatively, combination therapy in accordance with thepresent invention can be utilized with the same 5-FU dosage levels asmonotherapy with 5-FU, while achieving enhanced antineoplastic resultsalong with fewer side effects.

The invention is further illustrated by the following non-limitingexample.

EXAMPLE 1

The human colo-rectal cell lines SW 480 (primary), SW 620 (metastatic)and W 707 (metastatic) were incubated with the following: culture medium(control), taurolidine at 5, 10, 25, 50 and 100 pg/ml doses, and5-Fluorouracil (5-FU) at 5, 10, 25, 50 and 100 μM doses. 5-FU was testedalone, and together with taurolidine. Cell proliferation, apoptosis andcell cycle were assessed.

There was a significant decrease in tumor cell proliferation at 24hours. There was no significant increase in taurolidine-inducedapoptosis and taurolidine did not alter the phases of the cell cycle.There was an increase in LDH release (p=0.0011), which correlated withinhibited tumor proliferation. Taurolidine was found to augment theeffects of given doses of 5-FU (p=0.0001).

1. A method of inhibiting tumor growth in a cancer patient comprisingadministering to said patient a combination therapy comprising effectiveamounts of 5-Fluorouracil (5-FU) and a methylol transfer agent selectedfrom the group consisting of taurolidine, taurultam and a mixturethereof, wherein said methylol transfer agent substantially reduces thetoxic side effects of said 5-FU.
 2. The method of claim 1 wherein saidtumor is a lymphoma, carcinoma or sarcoma.
 3. The method of claim 1wherein said tumor is a glioma, a neuroblastoma, an astrocytoma,carcinomatous meningitis, breast cancer, ovarian cancer, prostatecancer, pancreatic cancer, CNS cancer, liver cancer, lung cancer,gastric cancer, esophageal cancer, urinary bladder cancer, leukemia,melanoma, renal cell cancer, cancer in a patient's head, or cancer in apatient's neck.
 4. The method of claim 6 wherein said tumor growth ismetastatic tumor growth.
 5. The method of claim 1 wherein said toxicside effects are selected from side effects on bone marrow, intestinalmucousa or oral mucousa, leukocyte or platelet count decreases,stomatitis, diarrhea, nausea, vomiting, neurological side effects,somnolence, ataxia, chest pain, myocardial necrosis, ischemia,inflammatory reactions, acute or chronic conjunctivitis, tear ductstenosis or ectropion.
 6. The method of claim 1 wherein said 5-FU andsaid methylol transfer agent are administered simultaneously, separatelyor sequentially.
 7. The method of claim 1 which comprises administeringsaid methylol transfer agent at a dosage of about 0.1 to about 1,000mg/kg.
 8. The method of claim 1 which comprises administering saidmethylol transfer agent at a dosage of about 10-20 grams.
 9. The methodof claim 1 which comprises administering said 5-FU at a dosage of about0.1-1,000 mg.
 10. The method of claim 1 which comprises administeringsaid 5-FU at a dosage of about 250 mg or 500 mg.
 11. The method of claim1 which comprises administering said 5-FU at a dosage of about 100-5,000mg/m² body surface area.
 12. The method of claim 1 which comprisesadministering said 5-FU at a dosage of about 200-1,000 mg/m² bodysurface area.
 13. The method of claim 1 which comprises administeringsaid 5-FU at a dosage of about 500-600 mg/m² body surface area.
 14. Acombination comprising 5-FU and a methylol transfer agent selected fromthe group consisting of taurolidine, taurultam and a mixture thereof,wherein said methylol transfer agent substantially reduces the toxicside effects of said 5-FU,
 15. The combination of claim 14 wherein said5-FU and said methylol transfer agent are administered simultaneously,separately or sequentially.
 16. A method of reducing the toxic sideeffects of 5-FU antineoplastic therapy in a cancer patient in needthereof, comprising administering to said patient an effective amount ofa methylol transfer agent selected from the group consisting oftaurolidine, taurultam and a mixture thereof to substantially enhancethe antineoplastic effects of said 5-FU and to reduce the 5-FU doseneeded to inhibit tumor growth and thereby reduce the toxic side effectsof said 5-FU antineoplastic therapy.
 17. The method of claim 16 whereinsaid tumor is a lymphoma, carcinoma or sarcoma.
 18. The method of claim16 wherein said tumor is a glioma, a neuroblastoma, an astrocytoma,carcinomatous meningitis, breast cancer, ovarian cancer, prostatecancer, pancreatic cancer, CNS cancer, liver cancer, lung cancer,gastric cancer, esophageal cancer, urinary bladder cancer, leukemia,melanoma, renal cell cancer, cancer in a patient's head, or cancer in apatient's neck.
 19. The method of claim 16 wherein said tumor is ametastatic tumor.
 20. The method of claim 16 wherein said toxic sideeffects are selected from side effects on bone marrow, intestinalmucousa or oral mucousa, leukocyte or platelet count decreases,stomatitis, diarrhea, nausea, vomiting, neurological side effects,somnolence, ataxia, chest pain, myocardial necrosis, ischemia,inflammatory reactions, acute or chronic conjunctivitis, tear ductstenosis or ectropion.
 21. The method of claim 16 wherein said 5-FU andsaid methylol transfer agent are administered simultaneously, separatelyor sequentially.
 22. The method of claim 16 which comprisesadministering said methylol transfer agent at a dosage of about 0.1 toabout 1,000 mg/kg.
 23. The method of claim 16 which comprisesadministering said methylol transfer agent at a dosage of about 10-20grams.
 24. The method of claim 16 which comprises administering said5-FU at a dosage of about 0.1-1,000 mg.
 25. The method of claim 16 whichcomprises administering said 5-FU at a dosage of about 250 mg or 500 mg.26. The method of claim 16 which comprises administering said 5-FU at adosage of about 100-5,000 mg/m² body surface area.
 27. The method ofclaim 16 which comprises administering said 5-FU at a dosage of about200-1,000 mg/m² body surface area.
 28. The method of claim 16 whichcomprises administering said 5-FU at a dosage of about 500-600 mg/m²body surface area.